Hyperglycemia in diabetes mellitus, if not controlled, over time causes certain irreversible morphologic changes including glomerular fibrosis in kidneys of affected subjects, a condition known as diabetic nephropathy that is associated with decline in renal function, eventually leading to end-stage renal disease. In type 1 (insulin-dependent) diabetes, glycemic control is usually achievable with chronic insulin therapy; however, in type 2 (non-insulin-dependent) diabetes, insulin alone may be ineffective in preventing hyperglycemia. Even in patients with type 1 diabetes, insulin sensitivity can be partially or completely lost. Insulin resistance, or loss of insulin sensitivity, is one of an array of physiological changes that occur in some individuals who are both obese and diabetic; such physiological changes are collectively known as metabolic syndrome. Diabetic nephropathy and metabolic syndrome are serious complications of diabetes that can dramatically reduce quality of life and survival time. A feature of both these complications is arterial hypertension, which superimposes risk of serious cardiac adverse events on the already high risk of chronic kidney failure arising from these complications.
Endothelins (ETs), particularly ET-1, are believed to play a role in mediating the damaging effects of hyperglycemia in the kidney and elsewhere. Expression of ET-1 in endothelial cells of the renal vasculature is upregulated by hyperglycemia; the potent profibrotic action of ET-1 thus generated in the kidney is believed to be involved in the morphologic changes seen in diabetic nephropathy. ET-1 acts via endothelin A (ETA) and endothelin B (ETB) receptors. Elevated plasma ET levels have been reported in patients with diabetes mellitus. See, for example, Takahashi et al. (1990) Diabetologia 33:306-310.
Elevated plasma ET levels have also been reported in patients with metabolic syndrome. See Ferri et al. (1997) Exp. Clin. Endocrinol. Diabetes 105:38-40. Metabolic syndrome (sometimes referred to as “syndrome X”) is characterized by coexistence of glucose intolerance, hypertension, dyslipidemia (specifically elevated LDL (low density lipoprotein) cholesterol and triglycerides and reduced HDL (high density lipoprotein) cholesterol), obesity and susceptibility to cardiovascular disease; these effects are thought to involve a common mechanism in which insulin resistance plays an important part.
The earliest clinical evidence of diabetic nephropathy is microalbuminuria, the appearance of low but abnormal levels (≧30 mg/day) of albumin in the urine. This early stage in development of the disease is known as incipient diabetic nephropathy. Without intervention, about 80% of subjects with type 1 diabetes who develop sustained microalbuminuria exhibit a progressive increase in urinary albumin, eventually (typically after 10-15 years) reaching clinical albuminuria (≧300 mg/day), a stage known as overt diabetic nephropathy. Accompanying the increase in albumin excretion is development of arterial hypertension. In subjects with overt diabetic nephropathy, without intervention, glomerular filtration rate (GFR) gradually falls over a period of 10-20 years, culminating in end-stage renal disease. See American Diabetes Association (2004) Diabetes Care 27 (suppl. 1):S79-S83. Structural changes in diabetic nephropathy include, in the incipient stage, mesangial expansion and a thickening of the glomerular basement membrane (GBM). An increase in glomerular and kidney size is generally observed. Later, during the overt stage, mesangial nodules and tubular interstitial fibrosis develop.
Hocher et al. (2001) Nephron 87:161-169 reported that in rats with streptozotocin-induced diabetes, administration of either the selective ETA receptor antagonist LU 135252 (darusentan) or the nonselective ETA/ETB receptor antagonist LU 224332, in both cases at a dose of 100 mg/kg/day, normalized glomerular matrix protein deposition, indicating an antifibrotic effect. However, neither compound was found to influence serum glucose concentrations in the course of the study.
Dhien et al. (2000) J. Pharmacol. Exp. Therap. 293:351-359 reported that LU 135252 at 100 mg/kg/day partially or fully reversed various renal effects of streptozotocin-induced diabetes in rats, including increased glomerular diameter and deposition of eosinophilic material within the glomeruli, but that plasma glucose levels were unaffected by LU 135252.
Sorokin & Kohan (2003) Am. J. Physiol. Renal Physiol. 285:F579-F589 remarked that the stage was set for clinical trials of ET inhibitors in patients with glomerular disease characterized by increased ET-1 production and actions.
Avosentan, which may be classified as a selective ETA or dual ETA/ETB receptor antagonist, has been reported to be in Phase III clinical development for diabetic nephropathy. See Battistini et al. (2006) Exp. Biol. Med. 231:653-695.
U.S. Pat. No. 6,197,780 to Münter & Kirchengast reported that treatment of obese mice with “substance 23” (darusentan) at 50 mg/kg/day completely prevented increase in body weight. A method is claimed therein for treating a patient having hyperlipidemia, comprising administering a therapeutically effective amount of an ET antagonist (e.g., darusentan) to the patient.
Balsiger et al. (2002) Clin. Sci. 103 (Suppl. 48):4305-4335 reported that in a rat model of type 2 diabetes, BSF 208075 (said to be a selective ETA receptor antagonist) reduced plasma glucose levels and improved plasma glucose clearance rates in hyperglycemic rats.
On the other hand, Shaw et al. (2006) Exp. Biol. Med. 231:1101-1105 reported that in a mouse model of non-obese type 1 diabetes, the selective ETA receptor antagonist LU 208075 (ambrisentan) did not reduce the elevated plasma glucose levels seen in untreated animals.
According to Berthiaume et al. (2005) Metab. Clin. Exp. 54:735-740, some studies have shown desensitization by ET-1 of insulin signaling, leading to a decrease in glucose uptake, while other studies have shown opposite results. A study is reported therein of effects of the selective ETA receptor antagonist atrasentan in a rat model of insulin resistance. At a dose of 5 mg/kg/day, atrasentan was reported to significantly reduce 3-hour fasting insulin level but not 3-hour fasting glucose level, and to significantly reduce ΔAUC, a measure of incremental area under the curve induced by a meal tolerance test, for glucose, insulin and glucose-insulin index. These results were said to demonstrate an improvement in glucose tolerance and insulin sensitivity and to suggest that chronic endothelin antagonism may have benefits in treatment of insulin resistance and/or diabetes. It was further reported that ETA receptor blockade by atrasentan led to an increase rather than a decrease in plasma ET-1 levels.
Shaw & Boden (2005) Current Vascular Pharmacology 3:359-363 reviewed evidence on effects of ET-1 and proposed that chronically elevated ET-1 levels may be a cause of insulin resistance and impaired glucose tolerance in early stages of type 2 diabetes, obesity and metabolic syndrome. Recent data were said therein to indicate that combined ETA/ETB receptor antagonists may function as effectively as selective ETA blockers. A need was proposed for prospective trials to assess whether ET-1 antagonists, either alone or in combination, are superior to other more conventional treatments such as insulin sensitizers and to evaluate effects of combined therapies on development of insulin resistance and progression of diabetes.
Subjects having diabetic nephropathy and/or metabolic syndrome represent a particularly challenging subpopulation of diabetic patients, for whom therapies giving improved outcomes with respect to quality of life and survival time, through enhanced glycemic control and/or insulin sensitivity, would represent an important advance in the art.
Recognizing that elevated blood pressure occurs in both diabetic nephropathy and metabolic syndrome, and brings its own attendant risks to quality of life and survival time, an even more challenging patient population comprises subjects having at least one of these complications of diabetes and exhibiting inadequate blood pressure control by standard antihypertensive therapies. Subjects exhibiting resistance to a baseline antihypertensive therapy with one or more drugs include patients having clinically diagnosed resistant hypertension. Resistant hypertension is defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7; Chobanian et al. (2003) Hypertension 42:1206-1252) as a failure to achieve goal blood pressure in patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic. Further, resistant hypertension is diagnosed by many physicians on the basis of a patient's resistance to adequate, but less than full, doses of an appropriate three-drug regimen because of the risk or occurrence of adverse events associated with full doses. The terms “adequate” and “full” in the present context are defined hereinbelow.
For patients with serious or compelling conditions such as diabetes and chronic kidney disease, JNC 7 recommends a goal of systolic blood pressure (SBP)<130 mmHg and diastolic blood pressure (DBP)<80 mmHg. Despite intensive, multi-drug therapy, only about 50% of patients with diabetes or chronic kidney disease reach traditional blood pressure goals, with even fewer reaching the more stringent goals now recommended by JNC 7. Thus, resistant hypertension is particularly acute for segments of the population which exhibit complications of diabetes such as diabetic nephropathy or metabolic syndrome.
It should be noted that the British Hypertensive Society (BHD-IV; J. Human Hypertens. (2004) 18:139-185), the European Society of Hypertension/European Society of Cardiology (ESH/ESC; J. Hypertens. (2003) 21:1011-1053), and the World Health Organization/International Society of Hypertension (WHO/ISH; J. Hypertens. (2003) 21:1983-1992) guidelines propose similar but not identical blood pressure goals for diabetic patients.
In a news release dated Aug. 18, 2005 (http://stockjunction.com/modules.php?name=News&file=print&sid=7332), Myogen Inc. reported positive results in a clinical trial (DAR-201) evaluating darusentan in resistant hypertension. Among inclusion criteria for DAR-201 were subjects with diabetes and/or chronic kidney disease with mean systolic blood pressure ≧130 mmHg (http://clinicaltrials.gov/ct/show/NCT00364026).
Weber et al. (2006) presented a poster, available at http://www.secinfo.com/dvjdn.vbz.d.htm, posted May 16, 2006, reporting, inter alfa, subject demographics in the DAR-201 study. Of 115 subjects enrolled, 70 had diabetes and/or chronic kidney disease, 55 had diabetes and 29 had chronic kidney disease.
Nakov et al. (2002) Am. J. Hypertens. 15:583-589 described a 392-patient study in which moderate hypertension was treated with darusentan at 10 to 100 mg/day. Exclusion criteria included concomitant medication with other antihypertensive drugs. Darusentan was reported to significantly reduce SBP and DBP by comparison with placebo.
German Patent No. DE 19744799 of Knoll mentions, in the abstract thereof, combinations of an endothelin antagonist, such as darusentan, and a diuretic said to show synergistic activity in treatment of hypertension, coronary artery disease, cardiac or renal insufficiency, renal or myocardial ischemia, subarachnoid hemorrhage, Raynaud's disease and peripheral arterial occlusion.
U.S. Pat. No. 6,352,992 to Kirchengast et al. proposes pharmaceutical combination preparations comprising a beta-receptor blocker and an endothelin antagonist for treatment of vasoconstrictive disorders. Among endothelin antagonists mentioned is darusentan.
German Patent No. DE 19743142 of Knoll proposes combinations of an endothelin antagonist, such as darusentan, and a calcium antagonist for treatment of cardiovascular disorders such as pulmonary hypertension and renal and myocardial ischemia.
U.S. Pat. No. 6,329,384 to Munter et al. proposes combinations of endothelin antagonists, such as darusentan, and renin-angiotensin system inhibitors, in particular angiotensin II antagonists and angiotensin converting enzyme (ACE) inhibitors for treatment of vasoconstrictive disorders such as hypertension, heart failure, ischemia or vasospasms.
German Patent No. DE 19743140 of Knoll proposes combinations of an endothelin antagonist, such as darusentan, and a vasodilator for treatment of cardiovascular disorders such as pulmonary hypertension, renal or myocardial ischemia, subarachnoid hemorrhage, Raynaud's disease, and peripheral arterial occlusion.
International Patent Publication No. WO 2004/082637 of Pharmacia proposes combinations of an aldosterone receptor antagonist with an endothelin receptor antagonist and/or an endothelin converting enzyme inhibitor, compositions thereof, and therapeutic methods for use in treatment of pathological conditions such as hypertension, cardiovascular disease and renal dysfunction.
Improved drug therapies for treatment of patients having complications of diabetes such as diabetic nephropathy and/or metabolic syndrome, especially such patients exhibiting resistance to a baseline antihypertensive therapy with one or more drugs, for example patients having clinically diagnosed resistant hypertension, would be highly desirable.